Proteasome systems in cell stress and inflammation
Our research programme evolves around how toxic agents that are associated with cell stress and neurodegeneration can be counterbalanced by the molecular recycling machines that are found abundantly in cells.
Aggregation of misfolded proteins is a pathological process implicated in neurodegenerative disorders and dementia. While much research effort has focused on how aggregates are assembled, the reverse process of aggregate removal is less well-studied. Using advanced microscopy and cell biology approaches, The Ye Lab studies how proteasomes maintain cell homeostasis by targeting aggregates and how the ubiquitin-proteasome system is impaired in disease. Our recent results in vitro and in cells demonstrate that proteasomes restrict aggregate size and reorganise upon cell stress, assembling into foci around aggregates in a cytoskeleton-dependent manner. We are now focusing on the mechanisms underlying proteasome responses during aggregate formation in neurons, ultimately establish approaches to restrict and reverse dementia.
Current research interests:
1. How do proteasomes target distinct types of aggregates in neurons?
2. What additional factors are associated with proteasomes during stress?
3. How do proteasomes respond to aggregate formation over time in patient-derived neurons?
We are keen to recruit enthusiastic scientists to lead these exciting projects!
Our long-term goal is to identify distinct functions within the ubiquitin-proteasome system that will be amenable to therapeutic intervention at the different stages of neurodegeneration.
The key objectives of this research programme are to:
1. Determine the processes and factors that help proteasomes during removal of toxic aggregates in neurons.
2. Characterise mechanisms of the proteasome system and how it is impaired in neurodegenerative disorders.
3. Target distinct functions of the proteasome system so as to prevent or reverse stress-associated aggregates.